Generally, an SMB adsorption separation process is well known as a technique which has been steadily developed since it was invented by the UOP Company in the 1960s and commercially applied to industrial-scale separations of various isomers in petrochemical processes. Further, the SMB technique has been widely employed in the industry fields concerned with pharmaceuticals and fine chemicals, as diverse chiral stationary phases are developed for use in separation of chiral compounds from the mid 1990s (G. Subramanian, Chiral Separation Techniques, Wiley-VCH, 2000).
The SMB adsorption process is carried out in four zones of desorption, purification, adsorption, and buffering, in which a feed injection port, an eluent injection port, an extract port and a raffinate port are provided between two neighboring zones. Moreover, the SMB process is designed to simulate a countercurrent flow of a fluid relative to a stationary phase by periodically switching the ports in the same direction as fluid flow. Hence, when compared to conventional techniques including enzymatic resolution, asymmetric synthesis, etc., the SMB process is advantageous because both (R)- and (S)-isomers can be simultaneously produced with high purities, and all the process operation conditions required for production of the two isomers having high purity are theoretically found (M. P. Pedeferri, Experimental analysis of a chiral separation through simulated moving bed chromatography, Chemical Engineering Science, vol. 54, 3735-3748, 1999).
In addition, the SMB separation process is reported to have the advantages of continuous operation, and easy recovery of solvent, resulting in higher productivity and a dramatic reduction in solvent consumption, compared to any conventional batch chromatography (R. M. Nicoud, The separation of optical isomers by Simulated Moving Bed Chromatography, Pharmaceutical Technology Europe, March-April, 1999).
Meanwhile, optically active thiophene-based compounds are fundamental materials which play an important role in the preparation of various pharmaceuticals. Particularly, dorzolamide developed by Merck & Co. is a very effective therapeutic agent for the treatment of glaucoma. Hence, methods of efficiently producing optically active thiophene-based compounds, in particular, dorzolamide and an intermediate thereof, are urgently required.
In this regard, the conventional methods of preparing optically active dorzolamide and an intermediate thereof are exemplified as follows:
U.S. Pat. No. 4,968,814 and J. Org. Chem. 1993, 58(7), 1672. disclose a method for preparing an intermediate of dorzolamide that is optically active, by reacting (R)-hydroxybutyric acid methyl ester used as a starting material with thiophene-2-thiol. The disclosed method is advantageous because it uses (R)-hydroxybutyric acid methyl ester having very high optical purity, obtained by the reaction of natural polymer with methanol. However, this method is disadvantageous because an additional chemical reaction is required to react the aforementioned starting material with thiophene-2-thiol, and also, the optical purity of the product is decreased by at least 2% compared to that of the starting material after the reaction with thiophene-2-thiol. Moreover, this method involves multiple reaction steps and the reaction conditions to be precisely controlled or adjusted, and thus, it is unsuitable for use in industrial-scale production.
Likewise, U.S. Pat. No. 4,968,815 discloses a method of preparing an intermediate of dorzolamide that is optically active, using optically active lactone. However, this method also has drawbacks, such as requiring the additional preparation of lactone, and reacting unstably. Therefore, the above method is not suitable for use in industrial-scale production.
Also, U.S. Pat. No. 4,797,413 and EP 0 296 879 B1 disclose a method of preparing optically active dorzolamide, through optical resolution of racemic trans-dorzolamide using a tartaric acid derivative. According to the above method, tartaric acid and its salts are prepared, recrystallized to increase optical purity, and then neutralized, to obtain a final product. The above method is disadvantageous because it requires somewhat complicated processes, and has relatively low yield and optical purity, resulting in being unsuitable for use in industrial-scale production.